CHARGE syndrome: The phenotypic spectrum of mutations in the CHD7 gene

Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands.
Journal of Medical Genetics (Impact Factor: 6.34). 05/2006; 43(4):306-14. DOI: 10.1136/jmg.2005.036061
Source: PubMed


CHARGE syndrome is a non-random clustering of congenital anomalies including coloboma, heart defects, choanal atresia, retarded growth and development, genital hypoplasia, ear anomalies, and deafness. A consistent feature in CHARGE syndrome is semicircular canal hypoplasia resulting in vestibular areflexia. Other commonly associated congenital anomalies are facial nerve palsy, cleft lip/palate, and tracheo-oesophageal fistula. Specific behavioural problems, including autistic-like behaviour, have been described. The CHD7 gene on chromosome 8q12.1 was recently discovered as a major gene involved in the aetiology of this syndrome.
The coding regions of CHD7 were screened for mutations in 107 index patients with clinical features suggestive of CHARGE syndrome. Clinical data of the mutation positive patients were sampled to study the phenotypic spectrum of mutations in the CHD7 gene.
Mutations were identified in 69 patients. Here we describe the clinical features of 47 of these patients, including two sib pairs. Most mutations were unique and were scattered throughout the gene. All patients but one fulfilled the current diagnostic criteria for CHARGE syndrome. No genotype-phenotype correlations were apparent in this cohort, which is best demonstrated by the differences in clinical presentation in sib pairs with identical mutations. Somatic mosaicism was detected in the unaffected mother of a sib pair, supporting the existence of germline mosaicism.
CHD7 mutations account for the majority of the cases with CHARGE syndrome, with a broad clinical variability and without an obvious genotype-phenotype correlation. In one case evidence for germline mosaicism was provided.

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Available from: Marjolijn Jongmans,
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    • "CHARGE syndrome occurs in approximately 1 in every 10,000 newborns worldwide, and almost all cases of CHARGE syndrome occur sporadically (Bergman et al., 2011). The recurrence rate is approximately 1% among sib-pairs, monozygotic twins, and 2-generation families (Jongmans et al., 2006; Lalani et al., 2006; Delahaye et al., 2007; Jongmans et al., 2008; Vuorela et al., 2008; Wincent et al., 2008; Pauli et al., 2009; Bergman et al., 2011). Familial CHARGE syndrome follows an autosomal dominant inheritance with variable penetrance (Bergman et al., 2011). "
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    ABSTRACT: Most cases of CHARGE syndrome are sporadic and autosomal dominant. CHD7 is a major causative gene of CHARGE syndrome. In this study, we screened CHD7 in two Turkish patients who had CHARGE syndrome symptoms as coloboma, heart defect, choanal atresia, retarded growth and ear anomalies and found a novel splice-site mutation (c.2443-2A>G) and a previously known frameshift mutation (c.2504_2508delATCTT). We performed exon trapping analysis to determine the effect of the c.2443-2A>G mutation at the transcriptional level, and found that it caused a complete skip of exon 7 and splicing at a cryptic splice acceptor site. Our current study is the second study demonstrating an exon 7 deficit in CHD7. Results of previous studies suggest that the c.2443-2A>G mutation affects the formation of nasal tissues and the neural retina during early development, resulting in choanal atresia and coloboma, respectively. The findings of the present study will improve our understanding of the genetic causes of CHARGE syndrome.
    Gene 11/2015; DOI:10.1016/j.gene.2015.11.006 · 2.14 Impact Factor
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    • "CHARGE syndrome is an autosomal dominant multi-system disorder involving coloboma, heart defects, choanal atresia, retarded growth and development, genital hypoplasia, ear anomalies and/or deafness (Jongmans et al., 2006). In 1998, Blake et al. established reformative diagnostic criteria for CHARGE syndrome comprising of major and minor criteria. "
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    ABSTRACT: In Genetics Out-patient Department of Shanghai Children's Medical Center, we consulted a 3-year-old boy with multiple anomaly syndrome (congenital heart disease, cryptorchidism, congenital deafness, mental retardation, exophthalmos, laryngeal cartilage dysplasia and high arched palate). We ruled out the possibility of multiple deformities caused by genomic imbalances. The patient was then clinically considered to have CHARGE syndrome, an autosomal dominant multi-system disorder involving defects in multiple organs, and CHD7 is the only known gene associated with the syndrome. Sequencing analysis of CHD7 of the proband identified a de novo heterogeneous mutation (c.2916_2917del, p.Gln972HisfsX22), a two-nucleotide deletion causing reading frame shift and resulting in a truncated CHD7 protein. Computational structure analysis suggests that the truncated protein only contains the chromodomains of CHD7, but lacks the SWI2/SNF2-like ATPase/helicase domain and the DNA binding domain, which are indispensable for the proper function of the protein, especially on chromatin remodeling. The patient then received follow up treatment in different clinical departments in a long period. To our best knowledge, this is the first CHARGE syndrome in Chinese patients diagnosed by gene analysis. In summary, the clinical symptoms and the description of treatment in the present case, combined with genetic test and functional prediction of CHD7, are helpful for further understanding and genetic counseling of the CHARGE syndrome.
    Meta Gene 12/2014; 2:469–478. DOI:10.1016/j.mgene.2014.06.002
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    • "CHARGE association is a multiple-malformation syndrome that includes ocular Coloboma, Heart malformations, choanal Atresia, Retardation of growth and development, Genital abnormalities and inner and external Ear abnormalities [1]. The majority of subjects with CHARGE association presents mutations involving the chromodomain helicase DNA-binding protein-7 (CHD7) gene on chromosome 8q12 [2]. "
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    ABSTRACT: CHARGE association is characterized by ocular Coloboma, Heart malformations, choanal Atresia, Retardation of growth and development, Genital abnormalities and inner and external Ear abnormalities. Growth failure is a frequent find mainly associated with feeding difficulties or systemic diseases. To date, GH deficiency has been reported in only few patients with CHARGE association however long-term effects of GH treatment, up to final height, have never been reported. We describe a patient with CHARGE association and GH deficiency treated with GH from the age of 3 years and 10 months up to adult height.
    Italian Journal of Pediatrics 06/2014; 40(1):51. DOI:10.1186/1824-7288-40-51 · 1.52 Impact Factor
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